US8987209B2ActiveUtilityPatentIndex 70
N-carboxyalkyl-auristatin and the use thereof
Est. expirySep 29, 2030(~4.2 yrs left)· nominal 20-yr term from priority
Inventors:LERCHEN HANS-GEORGEL SHEIKH SHERIFSTELTE-LUDWIG BEATRIXGOLFIER SVENSCHUHMACHER JOACHIMGNOTH JEAN MARKKRENZ URSULA
C07K 1/1077A61K 45/06A61P 35/00C07K 5/0205A61K 38/00A61K 38/08C07K 7/02A61K 38/07C07K 5/1021
70
PatentIndex Score
6
Cited by
61
References
16
Claims
Abstract
The present application relates to new derivatives of monomethylauristatin F, substituted on the N terminus by a carboxyalkyl group, processes for preparing these derivatives, their use for the treatment and/or prevention of diseases and to produce medication for the treatment and/or prevention of diseases, particularly hyperproliferative and/or angiogenic disorders such as cancer disorders, for example. Such treatments can occur as monotherapies or in combination with other medication or further therapeutic measures.
Claims
exact text as granted — not AI-modifiedThe invention claimed is:
1. A compound of formula (I)
or a salt or solvate thereof, wherein
L is a straight-chain (C 1 -C 12 )-alkandiyl, optionally substituted with methyl up to four times and in which (a) two carbon atoms is optionally connected to each other in 1,2-, 1,3-, or 1,4 relation, if necessary including carbon atoms that are located between them to form a (C 3 -C 6 )-cycloalkyl-ring or a phenyl ring or (b) up to three CH 2 groups not adjacent to each other are optionally substituted for an O,
R 1 is hydrogen or methyl,
R 2 is isopropyl, isobutyl, sec.-butyl, tert.-butyl, 1-hydroxyethyl, phenyl, benzyl, 4-hydroxybenzyl, 1-phenylethyl, diphenylmethyl, 1H-imidazol-4-ylmethyl, or 1H-indol-3-ylmethyl,
or
R 1 and R 2 , together with the carbon atom to which they are both connected, form a 2-phenylcyclopropan-1,1-diyl group of the formula
wherein
# marks the points of attachment with other parts of the molecule,
and
T is a group with formula —C(═O)—OR 3 , —C(═O)—NR 4 R 5 , —C(═O)—NH—NH—R 6 , or —CH 2 —O—R 7 in which
R 3 is hydrogen, (C 1 -C 6 )-alkyl or (C 3 -C 10 )-cycloalkyl, wherein (C 1 -C 6 )-alkyl is optionally substituted with phenyl, naphthyl, or (C 3 -C 10 )-cycloalkyl,
R 4 is hydrogen or (C 1 -C 6 )-alkyl,
R 5 is hydrogen, (C 1 -C 6 )-alkyl, or (C 3 -C 10 )-cycloalkyl, wherein (C 1 -C 6 )-alkyl is optionally substituted with phenyl,
or
R 4 and R 5 are connected to each other and, together with the nitrogen atom they are attached to, form a 5- to 7-membered, saturated aza-heterocyclic compound, which may optionally contain a further ring-heteroatom selected from the group consisting of >N—H, >N—CH 3 , or —O—; and wherein said further ring-heteroatom is located either at the 1,3- or 1,4-location in relation to the aforementioned nitrogen atom,
R 6 is (C 1 -C 6 )-alkyl, (C 1 -C 6 )-alkylcarbonyl, phenyl, or benzoyl, and
R 7 is (C 1 -C 6 )-alkyl, optionally substituted with phenyl, where phenyl is optionally substituted with (C 1 -C 6 )-alkoxycarbonyl or carboxyl.
2. The compound of claim 1 or a salt or solvate thereof, wherein
L is a straight-chain (C 1 -C 8 )-alkandiyl, in which (a) two carbon atoms are optionally linked to each other in 1,3 or 1,4 relation including one or two carbon atoms located between them to form a phenyl ring or (b) up to two CH 2 groups not adjacent to each other which is optionally substituted for an O,
R 1 is hydrogen,
R 2 is benzyl, 4-hydroxybenzyl, 1-phenylethyl, or 1H-indol-3-ylmethyl,
or
R 1 and R 2 , together with the carbon atom to which they are both connected, form a 2-phenylcyclopropan-1,1-diyl group of the formula
wherein
# marks the points of attachment with other parts of the molecule,
and
T is a group with formula —C(═O)—OR 3 , —C(═O)—NR 4 R 5 , —C(═O)—NH—NH—R 6 , or —CH 2 —O—R 7 in which
R 3 is hydrogen or (C 1 -C 4 )-alkyl, which is optionally substituted with phenyl, naphthyl, or (C 3 -C 10 )-cycloalkyl,
R 4 is hydrogen or methyl,
R 5 is hydrogen or (C 1 -C 4 )-alkyl, which is optionally substituted with phenyl,
or
R 4 and R 5 are connected to each other and together with the nitrogen atom they are attached to, form a piperidine- or morpholine ring,
R 6 is (C 1 -C 4 )-alkylcarbonyl or benzoyl,
and
R 7 is (C 1 -C 4 )-alkyl or benzyl, which, in the phenyl group, is optionally substituted with (C 1 -C 4 )-alkoxycarbonyl or carboxyl.
3. The compound of claim 1 or a salt or solvate thereof, wherein
L is a straight-chain (C 1 -C 6 )-alkandiyl,
R 1 is hydrogen,
R 2 is benzyl, 1-phenylethyl or 1-H-indol-3-ylmethyl,
or
R 1 and R 2 , together with the carbon atom they are both attached to, form a (1S,2R)-2-phenylcyclopropan-1,1-diyl group of the formula
wherein
#1 marks the point of attachment with the adjacent nitrogen atom
and
#2 marks the point of attachment of group T,
and
T is a group with formula —C(═O)—OR 3 , —C(═O)—NR 4 R 5 , —C(═O)—NH—NH—R 6 , or —CH 2 —O—R 7 in which
R 3 is hydrogen, methyl, ethyl, n-propyl, benzyl, or adamantylmethyl,
R 4 is hydrogen or methyl,
R 5 is hydrogen, methyl, ethyl, n-propyl, or benzyl,
R 6 is benzoyl,
and
R 7 is benzyl, which is optionally substituted with methoxycarbonyl or carboxyl in the phenyl group.
4. The compound of claim 1 or a salt or solvate thereof, wherein said compound has the formula (IA)
wherein L, R 1 , R 2 , and T have the meaning indicated in claim 1 , and the radicals R 1 and R 2 supporting C X -carbon atom has the pictured configuration.
5. A method for producing the compound of claim 1 , the method comprising providing a compound of formula (II)
wherein R 1 , R 2 , and T have the meaning indicated in claim 1 ;
and coupling in an inert solvent the compound of formula (II) either by
[A] base-induced alkylation with a compound of formula (III)
wherein
L has the meaning indicated in claim 1 ,
E 1 is hydrogen, (C 1 -C 4 )-alkyl, or benzyl,
and
X is a leaving group selected from the group consisting of chloride, bromide, iodide, mesylate, triflate, and tosylate,
to produce a compound of formula (IV)
wherein E 1 , L, R 1 , R 2 , and T are defined as above,
and wherein, should E 1 stand for (C 1 -C 4 )-alkyl or benzyl, the ester radical is removed, thereby producing a hydrogen at E 1 in (III), thus producing the carboxylic acid according to formula (I);
or
[B] treatment with a compound of formula (V)
wherein
E 1 is hydrogen, (C 1 -C 4 )-alkyl, or benzyl,
and
L A has the meaning indicated in claim 1 , however, with the alkyl chain-length shortened by one CH 2 -unit,
in the presence of a suitable reducing agent to produce a compound of formula (VI)
wherein E 1 , L A , R 1 , R 2 , and T are defined as above,
and wherein, should E 1 stand for (C 1 -C 4 )-alkyl or benzyl, the ester radical is removed, thereby producing a hydrogen at E 1 , thus producing the carboxylic acid of formula (I-B);
in which L A , R 1 , R 2 , and T are defined as above.
6. A pharmaceutical composition comprising a compound as defined in claim 1 , and further comprising one or more inert, non-toxic, pharmaceutically suitable agents.
7. The pharmaceutical composition of claim 6 , further comprising one or more additional cytostatic or cytotoxic agents.
8. A method for treatment of cancer or tumor diseases in humans or animals, said method comprising administering to a subject an effective amount of at least one compound of claim 1 .
9. A method for treatment of cancer or tumor diseases in humans or animals, said method comprising administering to a subject an effective amount of at least one pharmaceutical composition of claim 6 .
10. The compound of claim 1 , wherein said compound is selected from the group consisting of:
or a salt or solvate thereof.
11. The compound of claim 10 , wherein said compound is selected from the group consisting of:
or a salt or solvate thereof.
12. The compound of claim 10 , wherein said compound is selected from the group consisting of:
or a salt or solvate thereof.
13. The compound of claim 10 , wherein said compound is selected from the group consisting of:
or a salt or solvate thereof.
14. The compound of claim 10 , wherein said compound is selected from the group consisting of:
or a salt or solvate thereof.
15. The compound of claim 10 , wherein said compound is selected from the group consisting of:
or a salt or solvate thereof.
16. The compound of claim 14 , wherein the compound is
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